Abstract
Background
Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA)
receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia
when used as adjuvants to conventional antipsychotics but possibly not to clozapine.
In this study, we assessed whether high-dose glycine may also be therapeutically beneficial
when added to olanzapine and risperidone treatment.
Methods
Seventeen olanzapine- or risperidone-treated schizophrenia patients participated in
a double-blind, placebo-controlled, 6-week crossover treatment trial with .8 g/kg/day
glycine added to their ongoing antipsychotic medication. Clinical assessments were
performed biweekly throughout the study. Clinical laboratory parameters and amino
acid serum levels were monitored.
Results
Glycine treatment was well tolerated and resulted in a significant (p < .0001) 23% ± 8% reduction in negative symptoms. Significant improvements were also
registered in cognitive and positive symptoms. The negative symptoms improvement remained
significant even following covariation for changes in other symptom clusters and extrapyramidal
side effects. High posttreatment glycine serum levels significantly predicted (r = .60) clinical response.
Conclusions
These findings indicate that the efficacy of olanzapine and risperidone may be augmented
using high-dose adjuvant glycine treatment and suggest that these atypical antipsychotics
may affect NMDA receptor-mediated neurotransmission differently than clozapine.
Keywords
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References
- Diagnostic and Statistical Manual of Mental Disorders.4th ed. American Psychiatric Press, Washington, DC1994
- A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.Am J Psychiatry. 2001; 158: 1305-1313
- Preliminary study of glycine administration in patients with spasticity.Neurology. 1974; 24: 392
- Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4phenyl-tetrahydropyridine monkeys.J Pharmacol Exp Ther. 1999; 290: 1034-1040
- Schizophrenia and glutamate.in: Bloom F.E. Kupfer D.J. Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York1995: 1205-1214
- Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response.Biol Psychiatry. 1999; 46: 73-77
- Glycine and N-methyl-D-aspartate receptors.Pharmacol Rev. 1998; 50: 597-664
- A “glutamatergic hypothesis” of schizophrenia. Rationale for pharmacotherapy with glycine.Clin Neuropharmacology. 1989; 12: 1-13
- Glycine site agonists of the NMDA receptor.CNS Drug Reviews. 1995; 1: 227-260
- A placebo controlled trial of glycine added to clozapine in schizophrenia.Am J Psychiatry. 2000; 157: 826-828
- A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia.Biol Psychiatry. 1999; 45: 512-514
- A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia.Arch Gen Psychiatry. 1999; 56: 21-27
- Dose-finding trial of d-cycloserine added to neuroleptics for negative symptoms in schizophrenia.Am J Psychiatry. 1995; 152: 1213-1215
- ECDEU Assessment Manual for Psychopharmacology.U.S. Department of Health, Washington, DC1995
- Amino acid transmitter systems in schizophrenia and other psychotic disorders.in: D'haenen H. den Boer J.A. Willner P. Biological Psychiatry. John Wiley and Sons, London2002: 587-600 (Education and Welfare)
- Double blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.Br J Psychiatry. 1996; 169: 610-617
- Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.Arch Gen Psychiatry. 1999; 56: 29-36
- Reversal of phencyclidine-induced effects by glycine and glycine transport inhibitors.Biol Psychiatry. 1999; 45: 668-679
- Recent advances in the phencyclidine model of schizophrenia.Am J Psychiatry. 1991; 148: 1301-1308
- Amelioration of negative symptoms in schizophrenia by glycine.Am J Psychiatry. 1994; 151: 1234-1236
- Glycine potentiates the NMDA responses in cultured mouse brain neurons.Nature. 1987; 325: 529-531
- Positive and Negative Syndrome Scale (PANSS) Rating Manual.Social and Behavioral Sciences Documents, San Rafael, CA1987
- Developmental changes in NMDA receptor glycine affinity and ifenprodil sensitivity reveal three distinct populations of NMDA receptors in individual rat cortical neurons.J Neurosci. 1998; 18: 1935-1943
- Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes.Science. 1988; 241: 835-837
- Cerebrospinal fluid amino acid concentrations in chronic schizophrenia.Psychiatry Res. 1987; 20: 337-345
- Glycocoll treatment of progressive muscular dystrophy.Deutsch Arch Klin Med. 1933; 175: 25-37
- Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans.Arch Gen Psychiatry. 1994; 51: 199-214
- Subanesthetic doses of ketamine stimulate psychosis in schizophrenia.Neuropsychopharmacol. 1995; 13: 9-19
- Preliminary investigation of high-dose oral glycine on serum levels and negative symptoms in schizophrenia.Biol Psychiatry. 1996; 39: 213-215
- Five-factor model of schizophrenia.J Nerv Ment Dis. 1994; 182: 631-638
- Study of a new schizophrenomimetic drug, Sernyl.Arch Neur Psychiatry. 1959; 81: 363-369
- Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics.Neuropsychopharmacol. 1997; 17: 141-150
- NMDA receptor function and human cognition.Neuropsychopharmacol. 1996; 14: 301-307
- Treatment of progressive muscular dystrophy and similar muscular disturbances with glycine.Deutsch Arch Klin Med. 1933; 174: 487-517
- NR2B selection NMDA receptor antagonists.Curr Pharm Des. 2002; 8: 845-855
- The Brief Psychiatric Rating Scale.Psychol Rep. 1961; 10: 799-812
- Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia.Am J Psychiatry. 1999; 156: 145-147
- Glycine adjuvant therapy to conventional neuroleptic treatment in schizophrenia.Clin Neuropharmacol. 1989; 12: 416-424
- A rating scale for extrapyramidal side effects.Acta Psychiatrica Scand Suppl. 1970; 212: 11-19
- Glycine therapy in 7 cases of spasticity.Pharmacol. 1974; 12: 117-119
- Schizophrenia and glutamatergic transmission.Crit Rev Neurobiol. 1998; 12: 37-67
- Antagonism of phencyclidine-induced hyperactivity by glycine in mice.Neurochem Res. 1986; 11: 393-400
- Abnormal excitatory neurotransmitter metabolism in schizophrenic brains.Arch Gen Psychiatry. 1995; 52: 829-836
- d-serine added to clozapine for the treatment of schizophrenia.Am J Psychiatry. 1999; 156: 1822-1825
- d-serine added to antipsychotics for the treatment of schizophrenia.Biol Psychiatry. 1998; 44: 1081-1089
- Risperidone in treatment-refractory schizophrenia.Am J Psychiatry. 1999; 156: 1374-1379
Article info
Publication history
Accepted:
July 7,
2003
Received in revised form:
May 22,
2003
Received:
February 4,
2003
Identification
Copyright
© 2004 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
